HDL continues to attract interest because its level is inversely associated with the risk of cardiovascular disease. This may be attributed to its various potentially anti-atherogenic properties, such as reverse cholesterol transport, anti-inflammatory, anti-oxidative, and anti-thrombotic effects. Clinical studies have shown that low HDL-C is also found in non-alcoholic steatohepatitis (NASH). NASH shares several characteristics with atherosclerosis, including lipid accumulation, inflammation, and macrophage infiltration. The pathogenesis of NASH involves scavenger receptor-mediated uptake of ox-LDL by macrophages in the liver.
Cholesteryl ester transfer protein (CETP) is considered a therapeutic target for increasing HDL-C. Interest in CETP as a therapeutic target began as a result of the high HDL-C and low LDL-C observed in Japanese people carrying the homozygous, defective CETP gene who showed no evidence of premature atherosclerosis, even though they had hypercholesterolemia. This CETP is bound mainly to HDL particles and transfers cholesterol ester from HDL to triglyceride-rich lipoproteins. CETP action results in a CE enrichment of non-HDL lipoproteins, which could contribute to atherosclerosis. Small molecule CETP inhibitors, including dalcetrapib, evacetrapib, and anacetrapib that are at various phases of clinical development inhibit CETP activity and significantly increase HDL-C. However, torcetrapib failed in phase 3 clinical trials due to compound specific off-target effects, and dalcetrapib failed in phase 3 clinical trials due to less meaningful outcomes. Two other CETP inhibitors, evacetrapib and anacetrapib, are still under clinical trials. Inducing an immune response against specific self-peptides is potentially beneficial for the treatment of certain diseases. The drawbacks of peptide-based immunization include low immunogenicity of self-peptides, a low efficiency of chemical conjugation, and the heterogeneous nature of antigen preparations.
U.S. Pat. No. 7,074,407 B1 provides a method for increasing HDL cholesterol in a mammal by stimulating an immune response that inhibits the function of CETP. U.S. Pat. No. 6,284,533 B1 provides a plasmid-based vaccine based on the combination of DNA segments coding for one or more B cell epitopes of cholesteryl ester transfer protein (CETP) and one or more broad range helper T cell epitopes. US20090104211 provides a CETP mimotope which, in their amino acid sequence are completely different from the amino acid sequence of CETP or of fragments of CETP. U.S. Pat. No. 6,410,022 B1 relates to peptides comprising a helper T cell epitope portion and a B cell epitope portion for eliciting an immune response against endogenous cholesteryl ester transfer protein (CETP) activity to prevent or treat cardiovascular disease, such as atherosclerosis. WO2014003531 provides a novel vaccine composition of micellar nanoparticles consisting of carboxyl terminal of CETP peptide immunogen for intranasal administration for the treatment and/or prevention of atherosclerosis disease or non-alcoholic fatty liver resulting from an abnormal metabolism of circulating lipids. Although a number of antigens are developed, their immunogenicity and efficiency are not sufficient.
Therefore, there is still a need to develop a CETP peptide immunogen having advantageous immunogenicity.